title: The secretogranin II gene is a signal integrator of glutamate and dopamine inputs.
abstract: Cooperative gene regulation by different neurotransmitters likely underlies the long-term forms of associative learning and memory, but this mechanism largely remains to be elucidated. Following cDNA microarray analysis for genes regulated by Ca(2+) or cAMP, we found that the secretogranin II gene (Scg2) was cooperatively activated by glutamate and dopamine in primary cultured mouse hippocampal neurons. The Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and the mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 prevented Scg2 activation by glutamate or dopamine; thus, the Ca(2+) /MEK pathway is predicted to include a convergence point(s) of glutamatergic and dopaminergic signaling. Unexpectedly, the protein kinase A inhibitor KT5720 enhanced Scg2 activation by dopamine. The protein-synthesis inhibitor cycloheximide also enhanced Scg2 activation, and the proteasome inhibitor ZLLLH diminished the KT5720-mediated augmentation of Scg2 activation. These results are concordant with the notion that dopaminergic input leads to accumulation of a KT5720-sensitive transcriptional repressor, which is short-lived because of rapid degradation by proteasomes. This repression pathway may effectively limit the time window permissive to Scg2 activation by in-phase glutamate and dopamine inputs via the Ca(2+) /MEK pathway. We propose that the regulatory system of Scg2 expression is equipped with machinery that is refined for the signal integration of in-phase synaptic inputs. We proposed hypothetical mechanism for the regulation of the secretogranin II gene as a signal integrator of glutamate and dopamine inputs. Glutamate or dopamine activates the Ca(2+) /MEK/ERK pathway, which thus contributes to the signal integration. Concurrently, activation of the PKA inhibitor KT5720-sensitive pathway by dopamine leads to accumulation of the repressor protein X that is otherwise susceptible to proteasome degradation. This repression system may determine the time window permissive to the cooperative activation by in-phase glutamate and dopamine inputs.
authors.affiliation: Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Katsuro
authors.initials: K
authors.lastname: Iwase
authors.forename: Akinori
authors.initials: A
authors.lastname: Ishihara
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Andoh
authors.forename: Masaki
authors.initials: M
authors.lastname: Kato
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Eriko
authors.initials: E
authors.lastname: Matsumoto
authors.forename: Takaki
authors.initials: T
authors.lastname: Hiwasa
authors.forename: Dominique
authors.initials: D
authors.lastname: Muller
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Masaki
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D053381:Secretogranin II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002227:Carbazoles; D018377:Neurotransmitter Agents; D011758:Pyrroles; D012333:RNA, Messenger; D053381:Secretogranin II; C506138:secretogranin 2, mouse; D005973:Glutamine; D015759:Ionomycin; C057416:KT 5720; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium; D004298:Dopamine
keywords: dopamine; glutamate; hippocampus; neurotransmission; secretogranin II; signal integrator